Biochemical Journal最新文献_第2页

Protein S: a vitamin K-dependent factor bridging haemostasis, tissue homeostasis and cancer. 蛋白S：一种维生素k依赖因子，桥接止血、组织稳态和癌症。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/bcj20260110

Omar Benzakour,Yousra Kaissouni,Olivier E Pardo,Fatima Dkhissi

{"title":"Protein S: a vitamin K-dependent factor bridging haemostasis, tissue homeostasis and cancer.","authors":"Omar Benzakour,Yousra Kaissouni,Olivier E Pardo,Fatima Dkhissi","doi":"10.1042/bcj20260110","DOIUrl":"https://doi.org/10.1042/bcj20260110","url":null,"abstract":"Protein S (PROS1) is a vitamin K-dependent plasma glycoprotein that was originally described as a non-enzymatic cofactor of activated protein C in the regulation of blood coagulation. Over the past three decades, PROS1 has emerged as a pleiotropic signaling molecule with functions that extend far beyond hemostasis. PROS1 is a ligand for the TAM family receptor tyrosine kinases TYRO3 and MERTK and, as such, regulates diverse cellular processes including proliferation, migration, phagocytosis, vascular homeostasis, and immune modulation. These activities are mediated through both circulating and locally produced PROS1 and are pathological context-dependent. In the present review, we first summarize our current knowledge on the regulation of PROS1 gene expression and protein structure. We then discuss its established anticoagulant mechanisms alongside emerging activated protein C-independent functions. Finally, we examine key regulatory roles of protein S-TAM signaling in the vessel wall, central nervous system, inflammation, and cancer. Collectively, these findings position PROS1 as a molecular integrator of coagulation, immunity, and tissue homeostasis and underscore its relevance as both a biomarker and a potential therapeutic target in a broad range of pathophysiological contexts.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"40 1","pages":"1489-1507"},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148416572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biochemical principles of SMAD signaling across the animal kingdom. 动物王国中SMAD信号的生化原理。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/bcj20250135

Razeen Shaikh,Caitlin Frank,Nissa J Larson,Hung-Yuan Chen,Anuj Girish Pradhan,Kailee Mendiola,Donny Hanjaya-Putra,David M Umulis,Jeremiah Zartman,Gregory T Reeves,Linlin Li

{"title":"Biochemical principles of SMAD signaling across the animal kingdom.","authors":"Razeen Shaikh,Caitlin Frank,Nissa J Larson,Hung-Yuan Chen,Anuj Girish Pradhan,Kailee Mendiola,Donny Hanjaya-Putra,David M Umulis,Jeremiah Zartman,Gregory T Reeves,Linlin Li","doi":"10.1042/bcj20250135","DOIUrl":"https://doi.org/10.1042/bcj20250135","url":null,"abstract":"The bone-morphogenetic protein (BMP)-SMAD signal transduction pathway regulates fundamental cellular processes such as fate specification, tissue patterning, and stem cell homeostasis across metazoans and has a conserved signaling architecture. However, the quantitative dynamics of SMAD signaling and regulatory strategies governing pathway activity show a wide range of variation across developmental and stem-cell systems. In the present review, we summarize insights from six major biological contexts-Drosophila embryo, germline stem cells, and the larval and pupal wing discs; the Danio rerio (zebrafish) embryo; and human pluripotent stem cells-to compare how BMP signals are measured, manipulated, modeled, and integrated. We begin by outlining the canonical BMP signaling pathway and the mechanisms of BMP gradient formation across developmental systems, highlighting how conserved pathway components contribute to the formation of system-specific spatial profiles. We then summarize intracellular Smad dynamics and how endogenous pathway dynamics are measured through quantitative imaging of the phosphorylated Smad. Next, we examine how BMP signaling is interpreted through tiered transcriptional responses of downstream target genes. Next, we summarize the mechanistic and computational models of integrated gradient formation, signal transduction, and gene regulation across the presented systems. These insights reveal unifying design principles and performance objectives that govern BMP-SMAD signaling across species and cell types and frame open questions for future cross-species and translational studies.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"92 1","pages":"1509-1534"},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The pivotal discovery of a major plant adaptation to a changing climate. 一种主要植物适应气候变化的关键发现。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/BCJ20267777

Christine H Foyer, Robert T Furbank

{"title":"The pivotal discovery of a major plant adaptation to a changing climate.","authors":"Christine H Foyer, Robert T Furbank","doi":"10.1042/BCJ20267777","DOIUrl":"10.1042/BCJ20267777","url":null,"abstract":"The discovery of the C4 pathway laid the foundations of a revolution in plant biochemistry. The Hatch and Slack paper published in the Biochemical Journal described a specialized pathway of photosynthetic metabolism that minimizes the loss of carbon and nitrogen to maximize efficiency in hot, dry environments. Since that time, there has been an enormous increase in our understanding of the anatomical and biochemical modifications that facilitate C4 photosynthesis in different species. A key feature is the concentration of CO2 in the vicinity of the carboxylating enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase, thereby increasing photosynthetic efficiency by minimizing photorespiration. C4 photosynthesis is an excellent model for complex trait evolution in response to environmental change. The C4 pathway represents one of the most convergent of evolutionary phenomena, having evolved independently many times over in diverse families of angiosperms. Climate change is changing the balance between C3 and C4 vegetation types, influencing how ecosystems process carbon and respond to isotope discrimination. Moreover, the pioneering work of Hatch and Slack has formed the biochemical backbone for the C4 rice project, which is one of the most ambitious metabolic engineering initiatives to be attempted in plant science.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"483 8","pages":"1611-1614"},"PeriodicalIF":3.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanobodies against Plasmodium adhesins that block receptor engagement and malaria parasite invasion. 抗疟原虫黏附素的纳米体阻断受体结合和疟原虫入侵。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/BCJ20260354

Jaison D Sa, Jill Chmielewski, Amy Adair, Li Lynn Tan, Li-Jin Chan, Lucas Krauss, Kathleen Zeglinski, Quentin Gouil, John Z Chen, Colin J Jackson, Christoph Q Schmidt, Sarel J Fleishman, Phillip Pymm, Wai-Hong Tham

{"title":"Nanobodies against Plasmodium adhesins that block receptor engagement and malaria parasite invasion.","authors":"Jaison D Sa, Jill Chmielewski, Amy Adair, Li Lynn Tan, Li-Jin Chan, Lucas Krauss, Kathleen Zeglinski, Quentin Gouil, John Z Chen, Colin J Jackson, Christoph Q Schmidt, Sarel J Fleishman, Phillip Pymm, Wai-Hong Tham","doi":"10.1042/BCJ20260354","DOIUrl":"10.1042/BCJ20260354","url":null,"abstract":"Malaria is caused by Plasmodium parasites, and its clinical symptoms are a result of parasite invasion of red blood cells and the subsequent cycles of replication and proliferation. In human populations, Plasmodium vivax is responsible for the most widely distributed recurring malaria infections whereas Plasmodium falciparum inflicts the most mortality and morbidity. One well-characterized family of adhesins involved in red blood cell invasion is the reticulocyte-binding-like protein homolog family, known as the RBL superfamily that includes the PfRh family in P. falciparum and PvRBP family in P. vivax. Here we report a collection of nanobodies against three members of this adhesin family, PfRh5, PfRh4, and PvRBP2b. Nanobodies against these Plasmodium adhesins bind with high affinity across several epitopes and can block receptor engagement and inhibit parasite invasion of red blood cells. Using computational design, we generated stabilized PfRh4 variants that encompass the conserved scaffold present in the PfRh and PvRBP families of adhesins and show that several variants with improved expression retained binding to mouse monoclonal antibodies, nanobodies, and Complement Receptor 1, the human receptor for PfRh4. We also observed that most of the inhibitory nanobodies against the three antigens recognized the conserved structural scaffold that define this family of adhesins. These results demonstrate the potential of nanobodies to block malaria parasite invasion into red blood cells.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1473-1488"},"PeriodicalIF":3.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13358728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional divergence and conservation in the QueC protein family (PF06508): from tRNA modification to anti-phage defense. QueC蛋白家族（PF06508）的功能分化和保护：从tRNA修饰到抗噬菌体防御。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/BCJ20260244

Kaitlynn Libby, Crista Calia, Rahul Benda, Valérie de Crécy-Lagard, Geoffrey Hutinet

{"title":"Functional divergence and conservation in the QueC protein family (PF06508): from tRNA modification to anti-phage defense.","authors":"Kaitlynn Libby, Crista Calia, Rahul Benda, Valérie de Crécy-Lagard, Geoffrey Hutinet","doi":"10.1042/BCJ20260244","DOIUrl":"10.1042/BCJ20260244","url":null,"abstract":"The QueC protein family (PF06508) is best known for its role in the biosynthesis of 7-deazaguanine derivatives, including the tRNA modification queuosine and the DNA base 7-cyano-7-deazaguanine. Recent discoveries, however, reveal that this ancient scaffold has been repeatedly repurposed for distinct biological functions, including roles in anti-phage defense. Here, we combine sequence similarity networks with genomic neighborhood analyses to map the functional diversification of the PF06508 superfamily. We delineate the canonical QueC cluster and experimentally define a refined catalytic signature, identifying previously unrecognized residues essential for transfer RNA modification. Beyond the canonical function, we characterize the evolutionary repurposing of the QueC fold in anti-phage systems, distinguishing between the 'divergent specialist' QatC, which remodels the active site, and the 'minimalist conservationist' Cap9, which retains the ancestral catalytic core. We further uncover the expansion of the superfamily into additional biochemical pathways, including cofactor biosynthesis (e.g., LarE) and purine salvage. Together, these findings provide a comprehensive framework for understanding how the QueC scaffold has been adapted from small-molecule biosynthesis to roles in protein modification and phage defense.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1357-1367"},"PeriodicalIF":3.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13329287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual targeting of SLC6A14 and autophagy/macropinocytosis enhances therapeutic efficacy in pancreatic ductal adenocarcinoma. SLC6A14和自噬/巨噬作用的双重靶向可提高胰腺导管腺癌的治疗效果。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/BCJ20250155

Mosharaf Mahmud Syed, Devaraja Rajasekaran, Souad R Sennoune, Tanima Sharker, Oscar Sanchez, Mary Katherine Jurek, Longfa Kou, Ruijie Chen, Vadivel Ganapathy, Yangzom D Bhutia

{"title":"Dual targeting of SLC6A14 and autophagy/macropinocytosis enhances therapeutic efficacy in pancreatic ductal adenocarcinoma.","authors":"Mosharaf Mahmud Syed, Devaraja Rajasekaran, Souad R Sennoune, Tanima Sharker, Oscar Sanchez, Mary Katherine Jurek, Longfa Kou, Ruijie Chen, Vadivel Ganapathy, Yangzom D Bhutia","doi":"10.1042/BCJ20250155","DOIUrl":"10.1042/BCJ20250155","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is highly desmoplastic and undergoes metabolic reprogramming to sustain its growth and proliferation. Our laboratory has identified SLC6A14, an amino acid transporter, as a novel drug target for PDAC. Genetic deletion of SLC6A14 or its pharmacological blockade with α-MLT attenuates PDAC growth by inducing amino acid deprivation. However, nutrient stress, particularly amino acid deprivation, can induce nutrient scavenging mechanisms like autophagy and macropinocytosis, thereby undermining the full anticancer potential of SLC6A14 blockade. To address this, the current work was conducted to test whether SLC6A14 blockade induces autophagy and/or macropinocytosis and to further investigate whether dual inhibition of SLC6A14 (α-MLT) and autophagy/macropinocytosis (HCQ) would yield a better therapeutic outcome in PDAC as opposed to targeting SLC6A14 alone. In vitro assays (MTT and colony formation) revealed that the combination treatment significantly reduced PDAC cell viability and clonogenic potential as opposed to monotherapy. The treatment model subcutaneous xenograft in athymic nude mice demonstrated a superior therapeutic outcome with the combination regimen. Collectively, our study demonstrates that the afore-described combination therapy creates a metabolic trap wherein α-MLT induces nutrient stress, while HCQ prevents autophagic and macropinocytosis compensation, thus culminating in a more potent tumor attenuation. This dual blockade represents a hitherto unexplored treatment strategy for PDAC.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1369-1390"},"PeriodicalIF":3.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13329288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition by ATP regulates the activity of a CBASS anti-phage nucleotide cyclase. ATP抑制可调节CBASS抗噬菌体核苷酸环化酶的活性。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/BCJ20260457

Laura Gaskell-Mew, Stuart McQuarrie, Stephen A McMahon, Peter Wotherspoon, Shirley Graham, Tracey M Gloster, Malcolm F White

{"title":"Inhibition by ATP regulates the activity of a CBASS anti-phage nucleotide cyclase.","authors":"Laura Gaskell-Mew, Stuart McQuarrie, Stephen A McMahon, Peter Wotherspoon, Shirley Graham, Tracey M Gloster, Malcolm F White","doi":"10.1042/BCJ20260457","DOIUrl":"10.1042/BCJ20260457","url":null,"abstract":"The bacterial anti-phage immune system is complex, diverse, and in several important cases ancestral to that found in eukaryotes, including humans. One example is CBASS (cyclic oligonucleotide based anti-phage signalling system), a widespread bacterial defence that signals phage presence in the cell via cyclic nucleotide second messengers, activating ancillary effectors to combat infection. CBASS is homologous and ancestral to the eukaryotic cGAS/STING pathway for antiviral defence. The heart of the system is a nucleotide cyclase known as a cGAS/DncV-like nucleotidyltransferase, which is activated by phage infection. The mechanisms of activation of CBASS cyclases are diverse and in most cases not fully understood at a molecular level. Moreover, it is vital to keep these signal-generating enzymes fully inactive in the absence of phage infection to avoid auto-toxicity. Here, we report a structural and mechanistic study of a CBASS cyclase from Bacillus cereus. Using crystal structures of key reaction intermediates, coupled with kinetic analyses, we show that the substrate, ATP, plays a fundamental role in the inhibition of the non-activated form of the enzyme in vitro. We provide a molecular explanation for this regulation and explore the implications for the regulation of these important defence systems in bacterial immunity.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1617-1630"},"PeriodicalIF":3.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The RNA-binding protein HuR stabilizes survivin mRNA in human oesophageal epithelial cells. rna结合蛋白HuR稳定人食管上皮细胞中的survivin mRNA。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-08-05 DOI: 10.1042/BJ20110028_EOC

James M Donahue, Elizabeth T Chang, Lan Xiao, Peng-Yuan Wang, Jaladanki N Rao, Douglas J Turner, Jian-Ying Wang, Richard J Battafarano

引用次数: 0

Molecular dissection of the Cereibacter sphaeroides spheroidene monooxygenase. 球芽孢杆菌球芽单加氧酶的分子解剖。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-07-21 DOI: 10.1042/bcj20260276

Elizabeth C Martin,Karolina O Panas,Felix S Morey-Burrows,Jack H Salisbury,Joshua R Barrett,George A Sutherland,C Neil Hunter,Andrew Hitchcock

{"title":"Molecular dissection of the Cereibacter sphaeroides spheroidene monooxygenase.","authors":"Elizabeth C Martin,Karolina O Panas,Felix S Morey-Burrows,Jack H Salisbury,Joshua R Barrett,George A Sutherland,C Neil Hunter,Andrew Hitchcock","doi":"10.1042/bcj20260276","DOIUrl":"https://doi.org/10.1042/bcj20260276","url":null,"abstract":"In some purple phototrophic bacteria, the enzyme spheroidene monooxygenase (CrtA) catalyses the final step of carotenoid biosynthesis, introducing a keto group at the C2 position of spheroidene to produce spheroidenone. CrtA from the model purple bacterium Cereibacter (previously Rhodobacter) sphaeroides has a C-terminal extension consisting of a disordered, proline-rich sequence followed by a short region containing a significant proportion of glycine residues; the role of this extension is not understood. In addition to the accumulation of spheroidene, a C. sphaeroides ΔcrtA mutant generated in a previous study had a slower growth rate and made fewer photosynthetic complexes than the wild type strain. We show here that these phenotypes are largely due to a polar effect of the crtA deletion on the downstream bchID bacteriochlorophyll biosynthesis genes. We generated a crtA mutant where bchID expression was not interrupted and used this background to test a series of CrtA C-terminal truncations to identify the minimal enzyme that retains spheroidene monooxygenase activity. Using structural modelling we identify the histidine residue that acts as the axial ligand to a heme group required for spheroidene monooxygenase activity, and two threonine residues found proximal to the bound carotenoid. We show that the subtle growth phenotype of this new ΔcrtA mutant is due to the loss of the C-terminus of the enzyme rather than the altered carotenoid content of this strain. We further demonstrate that the C-terminal extension appears to mediate the association of CrtA with other membrane proteins, forming a range of high molecular mass complexes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"296 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A distinctive PDZ:β-hairpin interaction mediates AFDN complex with SCRIB and promotes binding to KRAS. 独特的PDZ:β-发夹相互作用介导AFDN复合物与SCRIB并促进与KRAS的结合。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-07-20 DOI: 10.1042/bcj20260336

Chang Hwa Jo,Regina Strakhova,Marilyn Goudreault,Gabriela Bernal Astrain,Matthew J Smith

{"title":"A distinctive PDZ:β-hairpin interaction mediates AFDN complex with SCRIB and promotes binding to KRAS.","authors":"Chang Hwa Jo,Regina Strakhova,Marilyn Goudreault,Gabriela Bernal Astrain,Matthew J Smith","doi":"10.1042/bcj20260336","DOIUrl":"https://doi.org/10.1042/bcj20260336","url":null,"abstract":"PDZ domains canonically recognize short C-terminal peptide motifs, but numerous non-canonical binding mechanisms have also been described. We previously identified a direct interaction between the cell polarity protein SCRIB and the RAS effector AFDN, mediated by the SCRIB PDZ1 and AFDN FHA domains, though a structural basis remained unresolved. Here, we use AlphaFold3 predictions to model the SCRIB:AFDN complex, revealing that binding is driven by a conserved β-hairpin motif C-terminal to the AFDN FHA domain. This β-hairpin engages the canonical peptide-binding groove of SCRIB PDZ1, contributing an antiparallel strand to extend the PDZ β-sandwich, inserting a phenylalanine into the hydrophobic pocket, and forming contacts that recapitulate a canonical PDZ:peptide complex. We validate the interface with NMR spectroscopy and biochemical assays and show that point mutations at either side of the interface can abolish complex formation. Unexpectedly, disruption of full-length AFDN:SCRIB binding in cells results in loss of interaction with the KRAS oncoprotein. The identified β-hairpin motif is highly conserved across deuterostomes but absent from most invertebrate AFDN orthologs, including Drosophila melanogaster - the organism in which AFDN/Canoe and SCRIB/Scribbled function has been most extensively characterized. The complex closely resembles the only previously described PDZ:β-hairpin structure, between the PDZ domain of Syntrophin and a motif from nNOS/NOS1. A proteome-wide search identifies hundreds of candidate internal PDZ-binding sites conforming to this β-hairpin motif, suggesting the mechanism may be significantly more widespread than currently appreciated.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"244 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148499036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0